DOI: 10.1523/jneurosci.5775-11.2012. Motor Neuron Rescue in Spinal Muscular Atrophy Mice Demonstrates That Sensory-Motor Defects Are a Consequence, Not a Cause, of Motor Neuron Dysfunction

Motor Neuron Rescue in Spinal Muscular Atrophy Mice Demonstrates That Sensory-Motor Defects Are a Consequence, Not a Cause, of Motor Neuron Dysfunction

10.1523/jneurosci.5775-11.2012

Crossref journal-article

Society for Neuroscience

The Journal of Neuroscience (393)

Abstract

The loss of motor neurons (MNs) is a hallmark of the neuromuscular disease spinal muscular atrophy (SMA); however, it is unclear whether this phenotype autonomously originates within the MN. To address this question, we developed an inducible mouse model of severe SMA that has perinatal lethality, decreased motor function, motor unit pathology, and hyperexcitable MNs. Using anHb9-Creallele, we increased Smn levels autonomously within MNs and demonstrate that MN rescue significantly improves all phenotypes and pathologies commonly described in SMA mice. MN rescue also corrects hyperexcitability in SMA motor neurons and prevents sensory-motor synaptic stripping. Survival in MN-rescued SMA mice is extended by only 5 d, due in part to failed autonomic innervation of the heart. Collectively, this work demonstrates that the SMA phenotype autonomously originates in MNs and that sensory-motor synapse loss is a consequence, not a cause, of MN dysfunction.

Bibliography

Gogliotti, R. G., Quinlan, K. A., Barlow, C. B., Heier, C. R., Heckman, C. J., & DiDonato, C. J. (2012). Motor Neuron Rescue in Spinal Muscular Atrophy Mice Demonstrates That Sensory-Motor Defects Are a Consequence, Not a Cause, of Motor Neuron Dysfunction. The Journal of Neuroscience, 32(11), 3818â3829.

Authors 6

Rocky G. Gogliotti (first)
Katharina A. Quinlan (additional)
Courtenay B. Barlow (additional)
Christopher R. Heier (additional)
C. J. Heckman (additional)
Christine J. DiDonato (additional)

References 51 Referenced 154

10.1016/j.jpeds.2009.01.071
10.1016/S0896-6273(01)80026-X
10.1093/hmg/ddq300
10.1093/hmg/ddp310
10.1093/hmg/ddn320
10.1371/journal.pone.0003209
10.1093/hmg/6.8.1205
10.1006/nbdi.1996.0010
10.1089/104303403321070874
10.1038/nbt.1610
10.1093/hmg/ddm379
10.1002/mus.10081
10.1371/journal.pone.0015887
10.1152/jn.00335.2005
10.1093/hmg/ddq330
10.1186/1472-6793-10-16
10.1152/jn.00647.2004
10.1152/jn.00996.2009
10.1038/71709
10.1038/nature10485
10.1523/JNEUROSCI.4434-08.2009
10.1016/j.neuron.2006.02.020
10.1113/jphysiol.2004.074138
10.1523/JNEUROSCI.1612-09.2009
10.1093/hmg/ddi078
10.1093/hmg/ddr275
10.1016/0092-8674(95)90460-3
10.1038/ng0797-265
10.1152/jn.00236.2003
10.1371/journal.pone.0015457
10.1093/hmg/ddn189
10.1111/j.1748-1716.2010.02188.x
10.1016/j.neuron.2010.12.032
10.1093/hmg/9.3.333
10.1093/hmg/ddm367
10.1093/hmg/ddr360
10.1002/1526-968X(200011/12)28:3/4<147::AID-GENE90>3.0.CO;2-G
10.1038/mt.2011.232 / Mol Ther / Bifunctional RNAs targeting the intronic splicing silencer N1 increase SMN levels and reduce disease severity in an animal model of spinal muscular atrophy by Osman (2011)
10.1523/JNEUROSCI.2208-10.2010
10.1172/JCI41615
10.1126/scitranslmed.3001777
10.1016/S0092-8674(00)81632-3
10.1113/jphysiol.2010.200659
10.1523/JNEUROSCI.4496-09.2010
10.1073/pnas.94.18.9920
10.1093/hmg/ddq329
10.1002/path.2566
10.1016/j.brainres.2006.12.055
10.1523/JNEUROSCI.0274-05.2005
10.1093/hmg/ddq340
10.1371/journal.pone.0011696

Dates

Type	When
Created	13 years, 5 months ago (March 14, 2012, 2:09 p.m.)
Deposited	2 years, 4 months ago (April 13, 2023, 4:58 p.m.)
Indexed	1 month, 3 weeks ago (July 2, 2025, 1:54 p.m.)
Issued	13 years, 5 months ago (March 14, 2012)
Published	13 years, 5 months ago (March 14, 2012)
Published Online	13 years, 5 months ago (March 14, 2012)
Published Print	13 years, 5 months ago (March 14, 2012)

Funders 0

None

BibTeX

@article{Gogliotti_2012, title={Motor Neuron Rescue in Spinal Muscular Atrophy Mice Demonstrates That Sensory-Motor Defects Are a Consequence, Not a Cause, of Motor Neuron Dysfunction}, volume={32}, ISSN={1529-2401}, url={http://dx.doi.org/10.1523/jneurosci.5775-11.2012}, DOI={10.1523/jneurosci.5775-11.2012}, number={11}, journal={The Journal of Neuroscience}, publisher={Society for Neuroscience}, author={Gogliotti, Rocky G. and Quinlan, Katharina A. and Barlow, Courtenay B. and Heier, Christopher R. and Heckman, C. J. and DiDonato, Christine J.}, year={2012}, month=mar, pages={3818–3829} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        7,
        2
      ]
    ],
    "date-time": "2025-07-02T17:54:27Z",
    "timestamp": 1751478867247
  },
  "reference-count": 51,
  "publisher": "Society for Neuroscience",
  "issue": "11",
  "license": [
    {
      "start": {
        "date-parts": [
          [
            2012,
            9,
            14
          ]
        ],
        "date-time": "2012-09-14T00:00:00Z",
        "timestamp": 1347580800000
      },
      "content-version": "vor",
      "delay-in-days": 184,
      "URL": "https://creativecommons.org/licenses/by-nc-sa/4.0/"
    }
  ],
  "content-domain": {
    "domain": [],
    "crossmark-restriction": false
  },
  "published-print": {
    "date-parts": [
      [
        2012,
        3,
        14
      ]
    ]
  },
  "abstract": "<jats:p>The loss of motor neurons (MNs) is a hallmark of the neuromuscular disease spinal muscular atrophy (SMA); however, it is unclear whether this phenotype autonomously originates within the MN. To address this question, we developed an inducible mouse model of severe SMA that has perinatal lethality, decreased motor function, motor unit pathology, and hyperexcitable MNs. Using an<jats:italic>Hb9-Cre</jats:italic>allele, we increased Smn levels autonomously within MNs and demonstrate that MN rescue significantly improves all phenotypes and pathologies commonly described in SMA mice. MN rescue also corrects hyperexcitability in SMA motor neurons and prevents sensory-motor synaptic stripping. Survival in MN-rescued SMA mice is extended by only 5 d, due in part to failed autonomic innervation of the heart. Collectively, this work demonstrates that the SMA phenotype autonomously originates in MNs and that sensory-motor synapse loss is a consequence, not a cause, of MN dysfunction.</jats:p>",
  "DOI": "10.1523/jneurosci.5775-11.2012",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2012,
        3,
        14
      ]
    ],
    "date-time": "2012-03-14T18:09:12Z",
    "timestamp": 1331748552000
  },
  "page": "3818-3829",
  "source": "Crossref",
  "is-referenced-by-count": 154,
  "title": "Motor Neuron Rescue in Spinal Muscular Atrophy Mice Demonstrates That Sensory-Motor Defects Are a Consequence, Not a Cause, of Motor Neuron Dysfunction",
  "prefix": "10.1523",
  "volume": "32",
  "author": [
    {
      "given": "Rocky G.",
      "family": "Gogliotti",
      "sequence": "first",
      "affiliation": []
    },
    {
      "given": "Katharina A.",
      "family": "Quinlan",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Courtenay B.",
      "family": "Barlow",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Christopher R.",
      "family": "Heier",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "C. J.",
      "family": "Heckman",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Christine J.",
      "family": "DiDonato",
      "sequence": "additional",
      "affiliation": []
    }
  ],
  "member": "393",
  "published-online": {
    "date-parts": [
      [
        2012,
        3,
        14
      ]
    ]
  },
  "reference": [
    {
      "key": "2023041303552666000_32.11.3818.1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.jpeds.2009.01.071"
    },
    {
      "key": "2023041303552666000_32.11.3818.2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0896-6273(01)80026-X"
    },
    {
      "key": "2023041303552666000_32.11.3818.3",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/hmg/ddq300"
    },
    {
      "key": "2023041303552666000_32.11.3818.4",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/hmg/ddp310"
    },
    {
      "key": "2023041303552666000_32.11.3818.5",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/hmg/ddn320"
    },
    {
      "key": "2023041303552666000_32.11.3818.6",
      "doi-asserted-by": "publisher",
      "DOI": "10.1371/journal.pone.0003209"
    },
    {
      "key": "2023041303552666000_32.11.3818.7",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/hmg/6.8.1205"
    },
    {
      "key": "2023041303552666000_32.11.3818.8",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/nbdi.1996.0010"
    },
    {
      "key": "2023041303552666000_32.11.3818.9",
      "doi-asserted-by": "publisher",
      "DOI": "10.1089/104303403321070874"
    },
    {
      "key": "2023041303552666000_32.11.3818.10",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/nbt.1610"
    },
    {
      "key": "2023041303552666000_32.11.3818.11",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/hmg/ddm379"
    },
    {
      "key": "2023041303552666000_32.11.3818.12",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/mus.10081"
    },
    {
      "key": "2023041303552666000_32.11.3818.13",
      "doi-asserted-by": "publisher",
      "DOI": "10.1371/journal.pone.0015887"
    },
    {
      "key": "2023041303552666000_32.11.3818.14",
      "doi-asserted-by": "publisher",
      "DOI": "10.1152/jn.00335.2005"
    },
    {
      "key": "2023041303552666000_32.11.3818.15",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/hmg/ddq330"
    },
    {
      "key": "2023041303552666000_32.11.3818.16",
      "doi-asserted-by": "publisher",
      "DOI": "10.1186/1472-6793-10-16"
    },
    {
      "key": "2023041303552666000_32.11.3818.17",
      "doi-asserted-by": "publisher",
      "DOI": "10.1152/jn.00647.2004"
    },
    {
      "key": "2023041303552666000_32.11.3818.18",
      "doi-asserted-by": "publisher",
      "DOI": "10.1152/jn.00996.2009"
    },
    {
      "key": "2023041303552666000_32.11.3818.19",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/71709"
    },
    {
      "key": "2023041303552666000_32.11.3818.20",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/nature10485"
    },
    {
      "key": "2023041303552666000_32.11.3818.21",
      "doi-asserted-by": "publisher",
      "DOI": "10.1523/JNEUROSCI.4434-08.2009"
    },
    {
      "key": "2023041303552666000_32.11.3818.22",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.neuron.2006.02.020"
    },
    {
      "key": "2023041303552666000_32.11.3818.23",
      "doi-asserted-by": "publisher",
      "DOI": "10.1113/jphysiol.2004.074138"
    },
    {
      "key": "2023041303552666000_32.11.3818.24",
      "doi-asserted-by": "publisher",
      "DOI": "10.1523/JNEUROSCI.1612-09.2009"
    },
    {
      "key": "2023041303552666000_32.11.3818.25",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/hmg/ddi078"
    },
    {
      "key": "2023041303552666000_32.11.3818.26",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/hmg/ddr275"
    },
    {
      "key": "2023041303552666000_32.11.3818.27",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0092-8674(95)90460-3"
    },
    {
      "key": "2023041303552666000_32.11.3818.28",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/ng0797-265"
    },
    {
      "key": "2023041303552666000_32.11.3818.29",
      "doi-asserted-by": "publisher",
      "DOI": "10.1152/jn.00236.2003"
    },
    {
      "key": "2023041303552666000_32.11.3818.30",
      "doi-asserted-by": "publisher",
      "DOI": "10.1371/journal.pone.0015457"
    },
    {
      "key": "2023041303552666000_32.11.3818.31",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/hmg/ddn189"
    },
    {
      "key": "2023041303552666000_32.11.3818.32",
      "doi-asserted-by": "publisher",
      "DOI": "10.1111/j.1748-1716.2010.02188.x"
    },
    {
      "key": "2023041303552666000_32.11.3818.33",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.neuron.2010.12.032"
    },
    {
      "key": "2023041303552666000_32.11.3818.34",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/hmg/9.3.333"
    },
    {
      "key": "2023041303552666000_32.11.3818.35",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/hmg/ddm367"
    },
    {
      "key": "2023041303552666000_32.11.3818.36",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/hmg/ddr360"
    },
    {
      "key": "2023041303552666000_32.11.3818.37",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/1526-968X(200011/12)28:3/4<147::AID-GENE90>3.0.CO;2-G"
    },
    {
      "key": "2023041303552666000_32.11.3818.38",
      "doi-asserted-by": "crossref",
      "first-page": "119",
      "DOI": "10.1038/mt.2011.232",
      "article-title": "Bifunctional RNAs targeting the intronic splicing silencer N1 increase SMN levels and reduce disease severity in an animal model of spinal muscular atrophy",
      "volume": "20",
      "author": "Osman",
      "year": "2011",
      "journal-title": "Mol Ther"
    },
    {
      "key": "2023041303552666000_32.11.3818.39",
      "doi-asserted-by": "publisher",
      "DOI": "10.1523/JNEUROSCI.2208-10.2010"
    },
    {
      "key": "2023041303552666000_32.11.3818.40",
      "doi-asserted-by": "publisher",
      "DOI": "10.1172/JCI41615"
    },
    {
      "key": "2023041303552666000_32.11.3818.41",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/scitranslmed.3001777"
    },
    {
      "key": "2023041303552666000_32.11.3818.42",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0092-8674(00)81632-3"
    },
    {
      "key": "2023041303552666000_32.11.3818.43",
      "doi-asserted-by": "publisher",
      "DOI": "10.1113/jphysiol.2010.200659"
    },
    {
      "key": "2023041303552666000_32.11.3818.44",
      "doi-asserted-by": "publisher",
      "DOI": "10.1523/JNEUROSCI.4496-09.2010"
    },
    {
      "key": "2023041303552666000_32.11.3818.45",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.94.18.9920"
    },
    {
      "key": "2023041303552666000_32.11.3818.46",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/hmg/ddq329"
    },
    {
      "key": "2023041303552666000_32.11.3818.47",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/path.2566"
    },
    {
      "key": "2023041303552666000_32.11.3818.48",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.brainres.2006.12.055"
    },
    {
      "key": "2023041303552666000_32.11.3818.49",
      "doi-asserted-by": "publisher",
      "DOI": "10.1523/JNEUROSCI.0274-05.2005"
    },
    {
      "key": "2023041303552666000_32.11.3818.50",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/hmg/ddq340"
    },
    {
      "key": "2023041303552666000_32.11.3818.51",
      "doi-asserted-by": "publisher",
      "DOI": "10.1371/journal.pone.0011696"
    }
  ],
  "container-title": "The Journal of Neuroscience",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://syndication.highwire.org/content/doi/10.1523/JNEUROSCI.5775-11.2012",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2023,
        4,
        13
      ]
    ],
    "date-time": "2023-04-13T20:58:34Z",
    "timestamp": 1681419514000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://www.jneurosci.org/lookup/doi/10.1523/JNEUROSCI.5775-11.2012"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2012,
        3,
        14
      ]
    ]
  },
  "references-count": 51,
  "journal-issue": {
    "issue": "11",
    "published-online": {
      "date-parts": [
        [
          2012,
          3,
          14
        ]
      ]
    },
    "published-print": {
      "date-parts": [
        [
          2012,
          3,
          14
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1523/JNEUROSCI.5775-11.2012"
  ],
  "URL": "http://dx.doi.org/10.1523/JNEUROSCI.5775-11.2012",
  "relation": {
    "has-review": [
      {
        "id-type": "doi",
        "id": "10.3410/f.714597896.790202829",
        "asserted-by": "object"
      }
    ]
  },
  "ISSN": [
    "0270-6474",
    "1529-2401"
  ],
  "subject": [],
  "container-title-short": "J. Neurosci.",
  "published": {
    "date-parts": [
      [
        2012,
        3,
        14
      ]
    ]
  }
}